The RecA-family recombinase Rad51 is the central player in homologous recombination (HR), the faithful pathway for repairing DNA double-strand breaks (DSBs) during both mitosis and meiosis. The behavior of Rad51 protein in vivo is fine-tuned via posttranslational modifications conducted by multiple protein kinases in response to cell cycle cues and DNA lesions. Unrepaired DSBs and ssDNA also activate Mec1^ATR and Tel1^ATM family kinases to initiate the DNA damage response (DDR) that safeguards genomic integrity. Defects in HR and DDR trigger genome instability and result in cancer predisposition, infertility, developmental defects, neurological diseases or premature aging. Intriguingly, yeast Mec1^ATR- and Tel1^ATM-dependent phosphorylation promotes Rad51 protein stability during DDR, revealing how Mec1^ATR can alleviate proteotoxic stress. Moreover, Mec1^ATR- and Tel1^ATM-dependent phosphorylation also occurs on DDR-unrelated proteins, suggesting that Mec1^ATR and Tel1^ATM have a DDR-independent function in protein homeostasis. In this minireview, we first describe how human and budding yeast Rad51 are phosphorylated by multiple protein kinases at different positions to promote homology-directed DNA repair and recombination (HDRR). Then, we discuss recent findings showing that intrinsic structural disorder and Mec1^ATR/Tel1^ATM-dependent phosphorylation are coordinated in yeast Rad51 to regulate both HR and protein homeostasis.

RecA 家族重组酶 Rad51 是同源重组 (HR) 的核心参与者，这是在有丝分裂和减数分裂期间修复 DNA 双链断裂 (DSB) 的可靠途径。Rad51 蛋白在体内的行为通过多种蛋白激酶响应细胞周期线索和 DNA 损伤进行的翻译后修饰进行微调。未修复的 DSB 和 ssDNA 还会激活 Mec1 ^ATR和 Tel1 ^ATM家族激酶以启动 DNA 损伤反应 (DDR)，从而保护基因组完整性。HR 和 DDR 的缺陷会引发基因组不稳定并导致癌症易感性、不孕症、发育缺陷、神经系统疾病或过早衰老。有趣的是，酵母 Mec1 ^ATR - 和 Tel1 ^ATM依赖磷酸化促进 DDR 期间 Rad51 蛋白的稳定性，揭示 Mec1 ^ATR如何减轻蛋白毒性应激。此外，Mec1 ^ATR和 Tel1 ^ATM依赖性磷酸化也发生在与 DDR 无关的蛋白质上，这表明 Mec1 ^ATR和 Tel1 ^ATM在蛋白质稳态中具有独立于 DDR 的功能。在这篇小综述中，我们首先描述了人类和出芽酵母 Rad51 如何在不同位置被多种蛋白激酶磷酸化，以促进同源定向的 DNA 修复和重组 (HDRR)。然后，我们讨论最近的发现表明内在结构紊乱和 Mec1 ^ATR / Tel1 ^ATM-依赖性磷酸化在酵母 Rad51 中协调以调节 HR 和蛋白质稳态。